ABSTRACT This added project is in response to NIA?s Notice NOT-AG-18-008 ??(AD/ADRD)-focused supplements for NIH grants that are not focused on Alzheimer?s disease?. Our active award targets the prohealing lipid autocrines/paracrines of macrophages and nerves (PLAMNs) to rescue the wound re-innervation using a model of old diabetic mice, especially the nanoparticle-sustained release of PLAMNs. Our findings include: the promotion of nerve regeneration and functions in diabetic wounds by PLAMNs; the deficiency of PLAMNs in diabetic wounds (contribute to impairment of re-innervation); and the sustained release of PLAMNs by amino-acid based polyesteramide (AA-PEA) nanoparticles (nanoPs) to compensate the PLAMN deficiency. A PLAMN induced neuronal survival and inhibited Alzheimer?s disease (AD) amyloidogenic processing. PLAMNs exist in the brains and blood of humans and mice without AD and diabetes, but are deficiency there of the AD counterparts. PLAMNs are partly responsible for the beneficial effects of their precursor DHA on chronic inflammatory diseases, including AD. PLAMNs are not yet used to treat AD patients or animal models. Our nanoPs have the promise to deliver PLAMNs to diabetic AD brains. Our data, and published results from others, suggest that PLAMNs, nanoPs, nanoP carried PLAMNs are safe to mice and/or humans. Diabetes is a high risk factor for developing AD. Diabetic wounds share many pathological features with AD, including neural death and chronic inflammation. Our objective here is to initially develop the nanoP delivery of PLAMNs into the brains for the future development of therapeutics for diabetes-exacerbated AD. We hypothesize that nanoPs can safely deliver PLAMNs into the brains of diabetic AD mice to compensate the PLAMN deficiency. Specific Aim 1: Assess and/or modify the nanoP-carried PLAMNs developed in this active award for the delivery of PLAMNs into the brains of diabetic AD mice. A) Determine the temporal basal levels of PLAMNs in brain of non-AD, non-diabetic mice compared to diabetic AD mice to establish a set of end-points to judge successful increase in PLAMNs in brains. B) Optimize the nanoPs, similar to what was planned in the active award, but aiming to deliver PLAMNs to brains of diabetic AD mice. Overall Impact: This added project will provide: 1) new knowledge on the effects of diabetes, AD, and diabetes and AD together on PLAMN levels in brains, which is the basis for the development of PLAMN delivery, and for future work on mechanisms and causal relationships in the inflammation and other processes that underlie these two disparate diseases that are thought to have common elements; 2) the AA-PEA nanoparticle delivery of PLAMNs to diabetic AD brains, a novel conceptual therapeutic lead to ameliorate diabetes-exacerbated AD. The work proposed is within the scope of the active award requiring only addition of parallel studies in a relevant animal model for which we already have access and research experience. The supplement award will enable us to do this work, to publish the novel overcome, and to submit a R01 application on diabetes-exacerbated AD following the publication.